Tositumomab/iodine-131 tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are radioimmunoconjugates targeting the CD20 antigen. Both agents are approved in the United States for use in relapsed or refractory, indolent or transformed, B-cell lymphoma. These agents are well tolerated and have the highest levels of single-agent activity observed in these histologies. This review will summarize the key trials that led to approval of both I-131 tositumomab and ibritumomab tiuxetan, and then focus on four novel therapeutic concepts in radioimmunotherapy: retreatment, therapy of de novo indolent lymphoma, therapy of aggressive histologies, and incorporation in high-dose therapy programs utilizing autologous stem cell support.
The review by Schaefer-Cutillo et al on radioimmunotherapy (RIT) of lymphoma highlights many of the important studies that justified the US Food and Drug Administration (FDA) approval of two RIT agents for relapsed/refractory low-grade or transformed low-grade lymphoma as well as the promising data from studies that have potential to expand the indications for RIT in the future. Indeed, all the data presented are remarkable in terms of the high response rates obtained and the years of durability of the responses. Yet, despite all these positive results, the use of RIT in medical practice appears to be a small fraction of what has been estimated that it could be. And this fraction may be in danger of further shrinkage with the recent withdrawal of promotion and marketing support of yttrium (Y)-90 ibritumomab tiuxetan (Zevalin) by its manufacturer.
Before I discuss this underutilization issue further, a few points specifically about this review are worth emphasizing and clarifying.
Points Deserving Emphasis
Schaefer-Cutillo et al give the impression that iodine (I)-131 tositumomab (Bexxar) and Y-90 ibritumomab tiuxetan are equivalent in efficacy and safety. Yet, as an example, they cite studies of RIT using these agents in rituximab (Rituxan)-refractory patients showing the median time to progression in responders to Y-90 ibritumomab tiuxetan of 8.7 months vs 24.5 months for responders to I-131 tositumomab. Other data, not directly compared in their report, concerning durability of responses in long-term responders (longer than 12 months) have shown longer time to progression with I-131 tositumomab (48.5 months) than with Y-90 ibritumomab tiuxetan (29.3 months). Granted, nothing short of a randomized comparative trial of the two agents will definitively determine whether differences exist, but available data need to be acknowledged rather than dismissed.
Moreover, there are potential reasons for these differences. They include, but are not limited to, the different epitopes of CD20 that these antibodies recognize, the different dosing strategies (individualized for clearance for I-131 tositumomab and by body weight for Y-90 ibritumomab tiuxetan), and the path length of the beta particles. It is entirely possible that one of these agents may be superior in certain situations (such as different tumor burdens or tumor sizes), but no studies have deciphered such differences to date.
Although Schaefer-Cutillo et al discuss the excellent results seen with RIT in the front-line setting for follicular lymphoma, it is important to note that very good results are achieved in the relapsed setting, especially if RIT is given earlier in the course of the disease rather than as a last resort. This is true for both agents. Indeed, when used as second-line treatment, complete response rates of up to 50% with remissions lasting years can be achieved. These results need to be considered in making choices among the various options available for patients as they experience the natural history of the disease.
With regard to front-line RIT in follicular lymphoma, although the results using RIT as consolidation after cytoreduction with chemotherapy are excellent, how different are they from using RIT as a single agent? Even when the high-risk Follicular Lymphoma International Prognostic Index (FLIPI) patients are compared between the Southwest Oncology Group (SWOG) combination trial and the single-agent I-131 tositumomab trial, the 5-year progression-free survival is the same, at 52%. This raises the issue of whether combination therapy is for everyone, especially considering the extra toxicity and time spent in treatment (several months vs 1 week).
Moreover, there are theoretical concerns about using RIT as it is currently administered in the setting of minimal residual disease (complete clinical remission). Because so much unlabeled antibody is administered during treatment, there is concern that unlabeled antibody may mask CD20-binding sites from the radioactive antibody. Future trials may need to explore different dosing regimens for patients in this setting. Another consideration is the order in which chemotherapy and RIT are given. Perhaps reversing the order-giving RIT first followed by chemotherapy as a mop-up-may take maximum advantage of both treatments. Still, single-agent RIT may be sufficient for some patients.
With all the positive data available on all frontsfrom relapsed/refractory to front-line low-grade, retreatment, aggressive lymphomas, and incorporation into stem cell transplantswhy is such effective treatment taking only 1 week to deliver being prescribed so seldom in clinical practice? There may be several reasons, none of them good. Since licensure for administration of radioisotopes is required, hematologists/oncologists must refer their patients to nuclear medicine or radiation oncology. Hematologists/oncologists may thus be reluctant to send their patients away temporarily and then get them right back to manage side effects. Under current reimbursement schemes, they would not receive revenue from the treatment administered.
Thus, there may be a tendency to first think of alternative treatments that can be administered in the office, such as rituximab (including maintenance rituximab), all things being medically equal in the eyes of the practitioner. Some practitioners may have little knowledge of this therapy or have information that is either wrong or misleading. For instance, the notion that RIT results in "burning bridges" for subsequent therapies including chemotherapy or hematopoietic stem cell transplant has been greatly exaggerated. Also, the issue of cost has been raised. But the cost of several months of treatment with chemotherapy with or without rituximab (maintenance or no maintenance) is likely to be higher (not counting time lost from work by the patient).
What are some possible solutions? Better education of the cancer community using correct information is one step. An easing of the licensure restrictions, more in line with what endocrinologists have for administering radioactive iodine, is another. Perhaps a realignment of reimbursement schemes might help. Whatever the solutions may be, it is important that we move forward on them or else RIT (and its further development not just for lymphoma, but for other diseases) and reviews like those of Schaefer-Cutillo et al may become only historical medical footnotes.
Mark S. Kaminski, MD
Dr. Kaminski is a member of the GlaxoSmithKline speakers bureau and is co-owner of the patent on Bexxar.